Lipid metabolism and adipose tissue function

脂质代谢和脂肪组织功能

• 批准号: 10532169
• 负责人: Jun Liu
• 金额: $ 50.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532169
• 关键词: Ablation; Acute; Adipocytes; Adipose tissue; Adult; Affect; Agonist; Apolipoproteins; Binding; Body Temperature; Body Weight; Body Weight decreased; Body fat; Brown Fat; Carbon; Cell Line; Cell model; Cells; Chronic; Data; Development; Energy Metabolism; Enzymes; Epidemic; Exhibits; Family; Fatty Acids; Fatty acid glycerol esters; Glucose; Goals; Guanosine Triphosphate Phosphohydrolases; Housing; Human; In Vitro; Insulin Resistance; Knock-out; Knockout Mice; Mammals; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Obesity; Organ; Oxygen Consumption; Pathogenesis; Phenotype; Physiological; Play; Prevalence; Proteins; Regulation; Respiration; Rodent; Role; Stable Isotope Labeling; Temperature; Testing; Thermogenesis; Tissues; Transgenic Mice; Transgenic Organisms; adipocyte differentiation; attenuation; cell type; combat; design; diet-induced obesity; dietary; energy balance; enzyme activity; fat burning; fatty acid oxidation; gain of function; glucose metabolism; glucose tolerance; improved outcome; in vivo; inhibitor; insight; insulin sensitivity; lipid metabolism; loss of function; member; mouse model; novel; novel therapeutic intervention; obese patients; oxidation; recruit; subcutaneous; transgene expression

Project Summary The prevalence of obesity has increased worldwide to epidemic proportions. Dysfunctional white adipose tissue (WAT) and brown adipose tissue (BAT) have been implicated in the pathogenesis of obesity and its related metabolic syndrome. BAT is densely packed with mitochondria and requires fatty acid (FA) oxidation to support thermogenesis. In comparison, WAT serves as a main energy storage organ and the FA oxidation in WAT is relatively low at ambient temperature. Chronic cold exposure induces browning of subcutaneous WAT to become thermogenic beige AT with increased FA oxidation capacity. Although FA oxidation is known to be a critical and fundamental metabolic end point in both humans and rodents, it is not completely clear how adipocyte FA oxidation is regulated post-translationally and how it contributes to whole-body energy metabolism in an autonomous manner. In this regard, our preliminary studies provide compelling evidence that a protein encoded by Apolipoprotein 6 (ApoL6) is a selective regulator of mitochondrial trifunctional protein (TFP), the key enzyme catalyzing FA β-oxidation. ApoL6 is highly expressed in WAT and differentiated adipocytes. In contrast, BAT normally expresses low levels of ApoL6, which increases during obesity or thermoneutrality-induced whitening. We found that in the basal condition, ApoL6 is localized to mitochondria, resulting in attenuation of mitochondrial FA oxidation. Transgenic mice expressing ApoL6 in BAT exhibited a lower thermogenic capacity upon cold exposure, and decreased energy expenditure along with increased adiposity. Conversely, adipose ApoL6 knockout mice on HFD showed a decreased body weight and fat mass gain. Based on these preliminary data, we hypothesize that by inhibiting mitochondrial FA oxidation and thereby decreasing energy expenditure, ApoL6 plays a key role in (1) maintaining fat storage in WAT and whole-body energy balance, and (2) impeding non-shivering thermogenesis in whitened BAT. There are three aims: In aim 1, we will determine the mechanistic role of mitochondrially localized ApoL6 in adipocyte FA oxidation by using gain- and loss-of-function cell models. In Aim 2 we will determine how adipose specific ApoL6 ablation in mice affects diet-induced obesity and its related metabolic changes including insulin resistance. In Aim 3 we will use both loss- and gain-of-function mouse models to define the role of ApoL6 in the regulation of BAT thermogenesis during obesity- and thermoneutrality-induced whitening. Evidence derived from this project should provide novel insight into the molecular basis for the regulation of FA oxidation and energy metabolism in adipose tissue, thereby advancing the possibilities for the development of novel therapeutic approaches to combat obesity and type 2 diabetes.

项目概要 肥胖症的患病率在世界范围内已达到流行病的程度。功能失调的白色脂肪 脂肪组织（WAT）和棕色脂肪组织（BAT）与肥胖及其发病机制有关。 相关代谢综合征。 BAT 富含线粒体，需要脂肪酸 (FA) 氧化才能 支持生热作用。相比之下，WAT 作为主要的能量储存器官，而 FA 氧化 WAT 在环境温度下相对较低。慢性寒冷暴露会导致皮下 WAT 褐变 变成产热米色 AT，并增加 FA 氧化能力。尽管已知 FA 氧化是 人类和啮齿动物的关键和基本代谢终点，尚不完全清楚如何 脂肪细胞 FA 氧化在翻译后受到调节及其如何贡献全身能量 以自主的方式进行新陈代谢。在这方面，我们的初步研究提供了令人信服的证据： 载脂蛋白 6 (ApoL6) 编码的蛋白质是线粒体三功能蛋白的选择性调节剂 (TFP)，催化FA β-氧化的关键酶。 ApoL6 在 WAT 中高表达并分化 脂肪细胞。相比之下，BAT 通常表达低水平的 ApoL6，在肥胖或 热中性诱导的美白。我们发现在基础条件下，ApoL6 定位于线粒体， 导致线粒体 FA 氧化减弱。在 BAT 中表达 ApoL6 的转基因小鼠表现出 暴露在寒冷环境下的产热能力较低，并且随着能量消耗的增加而减少 肥胖。相反，食用 HFD 的 ApoL6 脂肪敲除小鼠体重和脂肪量均有所下降 获得。基于这些初步数据，我们假设通过抑制线粒体 FA 氧化和 从而减少能量消耗，ApoL6 在 (1) 维持 WAT 中的脂肪储存和 全身能量平衡，(2) 阻碍增白 BAT 中的非颤抖产热作用。有三个 目标：在目标 1 中，我们将确定线粒体定位的 ApoL6 在脂肪细胞 FA 中的机制作用 通过使用功能获得和丧失功能的细胞模型进行氧化。在目标 2 中，我们将确定脂肪特异性如何 小鼠中 ApoL6 消除会影响饮食引起的肥胖及其相关代谢变化，包括胰岛素 反抗。在目标 3 中，我们将使用功能丧失和功能获得小鼠模型来定义 ApoL6 在 肥胖和热中性诱导的美白过程中 BAT 生热作用的调节。得出的证据 该项目应为 FA 氧化和调节的分子基础提供新的见解 脂肪组织中的能量代谢，从而促进开发新型药物的可能性 对抗肥胖和 2 型糖尿病的治疗方法。